Alkylaminoproline derivatives as alpha-2-delta-1 blockers

Abstract

The present invention relates to compounds showing pharmacological activity towards the subunit α2δ#of voltage-gated calcium channels (VGCC), especially the α2δ-1 subunit of voltage-gated calcium channels. More particularly, the invention relates to alkylaminoproline derivatives having this pharmacological activity, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain and/or as neuroprotective agents.

The invention claimed is: 
     
       1. A compound of formula (I): 
       
         
           
           
               
               
           
         
         a stereoisomer thereof, or a corresponding salt thereof, or a corresponding solvate thereof, wherein
 R 1  is selected from the group consisting of hydrogen, unsubstituted or substituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, and substituted or unsubstituted C 2-6  alkynyl; 
 A is —(CH 2 ) n —NR 2 R 2 ′, wherein n is 0, 1 or 2; 
 R 2  is unsubstituted C 1-6  alkyl; and 
 R 2′  is —(CH 2 ) m —R 3 , wherein
 m is 0, 1, 2 or 3; 
 R 3  is selected from the group consisting of unsubstituted or substituted aryl, unsubstituted or substituted cycloalkyl, and unsubstituted or substituted heterocyclyl, wherein the heterocyclyl is not a sulfur-containing heterocyclyl. 
 
 
       
     
     
       2. The compound according to  claim 1 , wherein R 1  is hydrogen. 
     
     
       3. The compound according to  claim 1 , wherein n is 0 or 1. 
     
     
       4. The compound according to  claim 1 , wherein R 2  is unsubstituted C 1-3  alkyl. 
     
     
       5. The compound according to  claim 1 , wherein m is 0 or 1. 
     
     
       6. The compound according to  claim 1 , wherein R 3  is unsubstituted or substituted aryl. 
     
     
       7. The compound according to  claim 1 , when the aryl, heterocyclyl or cycloalkyl in R 3  is substituted, the substituents are selected from halogen, unsubstituted C 1-6  alkyl, —OR′, —SR′, —SOR′, —SO 2 R′, —CN, —COR′, —COOR′, haloalkyl, haloalkoxy or —OC 1-6  alkyl wherein R′ is selected from the group consisting of hydrogen, OH and unsubstituted C 1-6  alkyl. 
     
     
       8. The compound according to  claim 1  wherein said compound is selected from the group consisting of:
 (2S,4S)-4-(Benzyl(methyl)amino)pyrrolidine-2-carboxylic acid; 
 (2S,4S)-4-((3-Chlorobenzyl)(methyl)amino)pyrrolidine-2-carboxylic acid; 
 (2S,4S)-4-((4-Fluorobenzyl)(methyl)amino)pyrrolidine-2-carboxylic acid; 
 (2S,4S)-4-((2-Fluorobenzyl)(methyl)amino)pyrrolidine-2-carboxylic acid; 
 (2S,4S)-4-(2,4-Difluorobenzyl)(methyl)amino)pyrrolidine-2-carboxylic acid; 
 (2S,4S)-4-((3,4-Difluorobenzyl)(methyl)amino)pyrrolidine-2-carboxylic acid; 
 (2S,4S)-4-((Methyl(phenyl)amino)methyl)pyrrolidine-2-carboxylic acid; and 
 (2S,4S)-4-((3-Chlorophenyl)(methyl)amino)pyrrolidine-2-carboxylic acid. 
 
     
     
       9. A process for the preparation of a compound of formula (I) wherein R 1  is hydrogen (Ia) said process comprising: 
       
         
           
           
               
               
           
         
         a) treating a compound of formula (IV) 
       
       
         
           
           
               
               
           
         
         with a compound of formula (Va) or a compound of formula (Vb) 
       
       
         
           
           
               
               
           
         
         in order to obtain a compound of formula (VI) 
       
       
         
           
           
               
               
           
         
         and 
         b) de-protecting the compound of formula (VI) obtained according to step a); 
         wherein R 1 , R 2  and R 2 ′ have the same meaning as indicated in  claim 1 , X represents a leaving group, Y represents R 1  or P 1 , wherein P 1  is a suitable protecting group, and P 2  represents a suitable protecting group for the amino function. 
       
     
     
       10. A pharmaceutical composition comprising a compound of  claim 1 . 
     
     
       11. A method for treating a disease or a disorder mediated by a subunit αδ said method comprising administering to a subject in need of such a treatment a compound of  claim 1 . 
     
     
       12. The method according to  claim 11 , wherein the disease or disorder comprises pain, depression, anxiety, or attention-deficit-/hyperactivity disorder (ADHD). 
     
     
       13. The method according to  claim 10 , wherein said compound is used as a neuroprotective agent. 
     
     
       14. The method according to  claim 13 , wherein said compound is used in the treatment of a neurological disorder concomitant with nervous system damage such as polyneuropathy, motor neuron diseases, movement disorders, disorders with neurocognitive impairment, cerebral-vascular accidents (CVAs), stroke, traumatic brain injury, spinal cord injury, multiple sclerosis or retinopathy. 
     
     
       15. A pharmaceutical composition comprising a compound according to  claim 1  or a pharmaceutically acceptable salt, a stereoisomer, prodrug, or solvate thereof, and at least a pharmaceutically acceptable carrier, additive, adjuvant, or vehicle. 
     
     
       16. The compound of  claim 1 , wherein said compound of formula (I) comprises an enantiomer, a diastereomer, or a racemic mixture. 
     
     
       17. The compound of  claim 1 , wherein said compound of formula (I) comprises an enantiomer or a diastereomer. 
     
     
       18. The compound of  claim 1 , wherein said compound of formula (I) comprises an enantiomically enriched mixture or a diastereomerically enriched mixture. 
     
     
       19. The method of  claim 11 , wherein said subunit αδ comprises a αδ-1 subunit of voltage-gated calcium channels. 
     
     
       20. The method of  claim 12 , wherein said pain comprises neuropathic pain, inflammatory pain, chronic pain, or other pain conditions involving allodynia or hyperalgesia or a combination thereof.